11-substituted,16alpha,17alpha-difluoromethylene steroids of the pregnane series



3,457,285 Patented July 22, 1969 ABSTRACT OF THE DISCLOSURE 16a,l7a-difluoromethylenepregn-4-ene derivatives substituted at C3 with keto, hydroxy, or esters and ethers thereof and at C-ll with keto, hydroxy, or chloro; optionally substituted at C-6 with methyl, fluoro, or chloro; at C-9 with fluoro or chloro; at C-16 with methyl; and at C21 with fluoro, hydroxy, or the esters and ethers thereof; and optionally unsaturated between C-1, 2 and/ or C-6, 7 are useful anti-inflammatories.

This is a continuation-in-part of copending application Ser. No. 486,226, filed Sept. 9, 1965, now U.S. Patent No. 3,338,928.

In particular, this invention pertains to cyclopentanophenanthrene derivatives.

Specifically, this invention pertains to substituted 161x, 17u-difluoromethylene steroids of the pregnane series which may be represented by the formula:

CH --R wherein each of Z and Z is a carbon-carbon single bond or a carbon-carbon double bond;

R is hydrogen, hydroxy, fiuoro, hydrocarbon carboxylic acyloxy, tetrahydrofuran-Z-yloxy or tetrahydropyran- 2-yloxy;

R is hydrogen or methyl;

R is hydrogen, methyl, fluoro or chloro;

R is hydrogen, fluoro or chloro;

R is oxygen or the group where R is hydrogen, hydroxy, hydrocarbon carboxylic acyloxy, tetrahydrofuran-Z-yloxy or tetrahydropyran 2-yloxy;

R" is oxygen or the group where R is hydroxy or chloro, R being chloro when R is chloro.

The compounds of the present invention possess antiinfiammatory properties and are useful in treatment of allergic diseases, collagen diseases, musculoskeletal diseases, skin diseases, and the like. The steroids may be administered by the conventional pharmacological forms such as orally topically, etc. An oral dosage unit in the range of about 0.001 mg. to about 10 mg. per kilogram of body weight is usually employed. These compounds may be administered in the usual forms such as powders, capsules, pellets, pills, solutions, syrups, and so forth. Topically, the compounds can be applied as powders, creams, ointments, solutions, aerosols, and so forth, containing about 0.001% to about 1% of the steroid with the remainder being an inert vehicle or combinations of inert vehicles. Optionally the steroid can be employed with other therapeutic agents.

The hydrocarbon carboxylic acyloxy groups of the steroids of the present invention contain less than 12 carbon atoms and are straight, branched, cyclic or cyclicaliphatic chain structures. The structures may be saturated, unsaturated, or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Typical esters thus include acetate, propionate, enanthate, caproate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, ,8 chloropropionate, adamantoate, and the like.

The compounds of the present invention are prepared in the following manner: a 20-keto-A -steroid, is treated with an equivalent amount, and preferably an amount greater than an equivalent amount, of an alkali metal or alkaline earth metal salt of the acid of the formula in which W is chloro, bromo, or iodo. Typical examples of such acid salts include: sodium chloroditluoroaceta'te, potassium iododifluoro acetate, etc. The reaction is carried out in an anhydrous, inert organic solvent of suflicient polarity to dissolve the reagent. Suitable solvents include: dimethyl diethylene glycol ether, 1,2-dimeth0xyethane, dimethyl triethylene glycol ether, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and the like. The process is conducted at temperatures sufficient to decompose the reagent, which is evidenced by the evolution of CO gas. As a rule, when sodium chlorodifluoroacetate is employed as a reagent, a temperature ranging from about C. to about C. is employed. The reaction time will vary depending upon the temperature, the amount of reagent used, the particular solvent used, and so forth. As a general rule, the reaction is completed within a period ranging from about 30 minutes to about 6 hours, but shorter or longer periods may be used. Optionally the reaction may be followed to completion by ultraviolet spectroscopy.

Under the conditions of the present process, hydroxy groups present on the starting material will be esterified, but these esterified hydroxy groups can be readily hydrolyzed with ethanolic potassium hydroxide, etc. Alternatively, the hydroxy groups can be protected prior to the process by esterification to hydrocarbon carboxylic acyloxy groups, or by etherification to tetrahydrofuran-Z- yloxy or tetrahydropyran-Z-yloxy groups.

At the completion of the process, the compounds may be isolated by conventional techniques. For example, the mixture is reduced to dryness, the residue is taken up in an inert organic solvent, immiscible with water, washed with water to neutrality, dried and reduced to dryness under vacuum to yield the product. The compound may be further purified by chromatography and/or recrystallization.

The 16-methyl-A -steroid starting materials of the present invention are produced by treating 3,20-diketo-l7ahydroxy steroids with semicarbazide to produce the 3,20- bis-semicarbazone steroid. The steroid is treated with acetic anhydride in glacial acetic acid and then is allowed to react with an aqueous solution of pyruvic acid to yield the 3,2O-diket0-A -c0rnp0und. This A -steroid is then caused to react with diazomethane to produce the 16,17- pyrazoline steroid which is pyrolized to yield the 16- methyl-A -steroid.

If the starting material possesses other unsaturation besides the d -unsaturation, side reactions may occur with the reagent. In a preferred embodiment of the invention, such other unsaturation will be protected. For instance, a A -steroid may be selectively halogenated with chlorine to produce the corresponding 5a,6,3-dichloro steroid. The dichloro steroid can be dehalogenated after the principal reaction, for example, with zinc and glacial acetic acid to yield the unsaturated steroid.

The 3-hydroxy-A -steroid can be converted into the 3- keto-A -steroid by treating the former with aluminum isopropoxide in cyclohexanone. Alternatively, the A -unsatu ration and/ or the A -unsaturation and/ or the M-unsaturation can be introduced into the saturated steroids at this time.

The A -unsaturation is introduced by treating the 3- keto steroid with bromine to yield the 3-keto-4-bromo steroid which yields the desired product upon debromination with lithium chloride. The A -unsaturation is introduced by treating the 3-keto-A -steroid with 2,3-dichloro- 5,6-dicyano-1,4 benzoquinone or selenium dioxide. The duced by treating the 3-keto-A -steroid with 2,3-dichloro- A -unsaturation is introduced by treating the 3-keto-A or 3- keto-A -steroid with chloranil.

The 6-chloro group is introduced by treating the 3- ethoxy-A -steroid with N-chlorosuccinimide. The 6B-chloro group is predominately formed, but this can be isomerized to the 6at-Chl0l'0 group by treatment with hydrogen chloride at about C. The 6-fluoro group is similarly introduced by using perchlorly fluoride as the reagent. The 9a-chloro and fluoro groups are introduced by treating the 96,11fl-oxido steroids with either hydrogen chloride or hydrogen fluoride respectively. The 9,8,11,8-oxido steroid is formed by treating the llfi-steroid with mesylchloride in the presence of an organic base, and the resulting A steroid is treated with N-bromoacetamide in the presence of perchloric acid, and then with potassium acetate to yield the desired product. The 9a,11}3-dichloro steroid is prepared by treating the A -steroid with chlorine gas.

The 2l-fluoro group is introduced by treating the 21- hydroxy steroid with methane sulfonyl chloride to yield the 2l-methane sulfonate steroid, which yields the 2l-iodo steroid when treated with sodium iodide. By treating the 21-iodo steroid with silver fluoride, the 2l-fluoro steroid is produced. Alternatively, by treating the 2l-iodo steroid with potassium acetate, the 21-acetoxy steroid is produced.

The 3-keto group present on the steroids may be converted into a 3fi-hydroxy group upon treatment with sodium borohydride under anhydrous conditions. The 35- and/ or the 21-hydroxy steroids may be readily esteritied by conventional techniques, such as with acetic anhydride in pyridine. The 3 B- and/ or 21-(tetrahydrofuran-Z-yloxy) and the Bfland/or 21-(tetrahydropyran-Z-yloxy) steroids are prepared by treating the 36- and/or 21-hydroxy steroids with either dihydrofuran or dihydropyran respectively in the presence of an acid catalyst, such as p-toluenesulfonyl chloride.

In order that those skilled in the art may more fully understand the present invention, the following examples are set forth. The examples are intended to merely illustrate the present invention and in no way should they be construed as expressing a limitation thereof.

PREPARATION I One gram of 17ac-hydroxy-21-acetoxypregnane-3,11,20- trione is treated with 1.4 g. of semicarbazide hydrochloride in 30 ml. of methanol containing 1 ml. of water and 0.74 g. of sodium bicarbonate. The mixture is refluxed for 3 hours and then maintained at 45 C. for an additional 20 hours while under a nitrogen atmosphere. Fifty milliliters of water are added, and the 3,20-bis-semicarbazone steroid is collected by filtration, dried, dissolved in a solution of 20 ml. of acetic acid and 1 ml. of acetic anhydride and heated at reflux under nitrogen for 1 hour.

The solution is reduced to dryness and a solution of 1 g. of sodium borohydride, 15 ml. of methanol and 20 ml. of tetrahydrofuran is added to the residue and it is allowed to stand for 15 hours. The mixture is reduced to dryness after 3 ml. of acetic acid are added. The residue is diluted with water, extracted with ethyl acetate, dried and reduced to dryness. The residue is placed in 12 ml. of acetic acid and treated with 6 ml. of water and 3 ml. of pyruvic acid. The mixture is allowed to stand at room temperature for 40 hours and at 60 C. for 2 hours and is then diluted with water and extracted with chloroform. The extracts are washed with water, an aqueous 5% potassium bicarbonate solution and water, dried and evaporated to dryness. The A -steroid is then placed in a solution of 2 ml. of acetic anhydride and 4 ml. of pyridine. After it is allowed to stand for 12 hours, the mixture is added to water, and the solid that forms is collected by filtration, washed and dried. The residue is dissolved in 10 ml. of ether, and a 10 ml. saturated ether solution of diazomethane is cautiously added to it. The mixture is evaporated to dryness, and the residue is gradually heated to 180 C. in vacuo, yielding 1lfl-hydroxy-l-methyl-Zlacetoxypregn-l6-ene-3,20-dione.

In a similar manner, 6a-methyl-17a-hydroxy-2l-acetoxypregn-4-ene-3,11,20-trione is converted into 6a,16-dimethyl-2l-acetoxypregna-4,16-diene-3,11,20 trione. By omitting the diazomethane and pyrolysis treatment, 60:- rnethyl-Zl-acetoxypregna-4,l6-diene-3,11,20-trione is obtained.

PREPARATION II A mixture of 1 g. of 6u-methyl-llfi-hydroxy-Zl-acetoxypregna-4,16-diene-3,20-dione, 25 ml. of benzene, 5 ml. of ethylene glycol and 50 mg. of p-toluenesulfonic acid is refluxed for 16 hours. The mixture is then washed with an aqueous sodium bicarbonate solution and water, dried and evaporated to dryness to yield 3,20-bisethylenedioxy- 6ot-methyl-21-acetoxypregna-5,16-dien-1 1 3-0]. The steroid is added to 15 ml. of chloroform, cooled to 0 C. and treated with 1.05 molar equivalents of chlorine. The mixture is allowed to reach 25 C.; then it is flushed with dry air, washed with aqueous sodium bicarbonte solution and water, dried, evaporated to dryness, and added to a solution of 50 ml. of acetone and 0.2 ml. of hydrochloric acid. After the mixture has stood for 15 hours, it is added to water and extracted with methylene chloride. The extracts are washed to neutrality, dried and evaporated to dryness to yield 5m,6fi-dichloro-6a-methyl-2l-acetoxypregn-16-ene-3,1 1,20-trione.

Example I To a stirred and refluxing solution of 1 g. of 3,20-bisethylenedioxy-6-methyl-21-acetoxypregna-5,16-dien 1 1;?- ol in 8 ml. of dimethyl diethyleneglycol ether is added in a dropwise fashion over a two-hour period, a solution of 30 equivalents of sodium chlorodifluoroacetate in 30 ml. of dimethyl diethyleneglycol ether. At the end of the reaction period, which may be followed by the UV. spectra, the mixture is filtered and evaporated in vacuo to dryness. The residue is added to 10% methanolic potassium hydroxide and this mixture is heated briefly at reflux and poured into ice water. The solid which forms is collected, washed with water, dried and chromatographed on alumina, eluting with methylene chloride, to yield 3,20- bisethylenedioxy--methyl 16a,l7a difluoromethylenepregn-5-diene-21,1lfi-diol.

A mixture of 0.5 g. of 3,20-bisethylenedioxy-G-methyl- :,1704- difluoromethylenepregn-S-ene-Z1,1IB-diol in 25 ml. of acetone and 0.1 ml. of concentrated hydrochloric acid is allowed to stand at room temperature for 15 hours and is then poured into water. This mixture is extracted with methylene chloride and the extracts are in turn washed with water to neutrality, dried over sodium sulfate and evaporated to dryness, to yield 6oi-methyl-11fi,21-

dihydroxy 1601,17 difiuoromethylenepregn-4-ene-3,20- dione which may be recrystallized from acetonezhexane.

A mixture of 1 g. of 6a-methyl-11,3,21-dihydroxy- 16a,17a-difluoromethylenepregn-4-ene-3,20-dione, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 6a-methyl-11,8-hydroxy-16a,17a-difluoromethylene-21-acetoxypregn 4 ene 3,20 dione which may be further purified through recrystallization from acetone: hexane.

Example II To a stirred and refluxing solution of l g. of 11B,2ldihydroxypregn-16-ene-3,20-dione in ml. of dimethyl triethylene glycol ether, is added in a dropwise fashion and under nitrogen, a 50% w./v. solution of sodium chlorodifiuoroacetate in the same solvent. When the addition of 5 equivalents of reagent fails to produce an appreciable change in the UV. spectrum, the addition is stopped. The solution is cooled and filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue thus obtained is chromatographed on alumina, eluting with methylene chloride, to yield 115,21- bischlorodifluoroacetoxy 1604,17 difluorornethylenepregnane-3,20-dione.

The product is then taken up in 50 ml. of methanol, cooled to 5 C., and then the resulting mixture is treated with a 5% solution of potassium hydroxide in 1 ml. of water. After 3 hours, the reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality and dried to yield 11,8,21-dihydroxy 1604,1704 difiuoromethylenepregnane-3,20-dione which is recrystallized from methylene chloride: ether.

In the same manner, 11oc,21 -dihydroxy-l6a,17a-difluoromethylene 16;? methylpregnane-3,20-dione is prepared from 115,21 dihydroxy 16 methylpregn-16-ene- 3,20-dione.

Example III To a stirred solution of 1 g. of 11fl,21-dihydroxy- 160:,170t-dlfi11010II1EthYlfi116 16/3 methylpregnane-3,20- dione in 17 ml. of chloroform and 20 ml. of glacial acetic acid, cooled to -10 C., are added a few drops of a solution of hydrogen bromide in 12 ml. of chloroform, the latter at such a rate that the reaction mixture maintains a pale yellow color. A cold solution of 2.5 g. of sodium acetate in 17 ml. of water is then added. The layers are separated and the aqueous layer is extracted with chloroform. The combined extracts and organic layer are washed with water, dilute potassium bicarbonate solution and with water, dried over sodium sulfate and evaporated to dryness to yield the 4-bromo intermediate, 1 g. of which is dissolved in ml. of dimethylformamide containing 0.5 g. of lithium chloride. This solution is stirred under nitrogen at steam bath temperatures for four hours. After cooling to 10 C., 11 ml. of water are added with stirring at such a rate that the temperature is maintained below 30 C. Stirring in an ice bath is continued until solid forms and this material is then collected by filtration, washed with cold 1:1 water:dimethylformamide and then water and dried to yield 11,8,21-dihydroxy-16a,17a-difiuoromethylene-16 3-methylpregn-4-ene-3,20-dione which is further purified through recrystallization from acetone with charcoal decolorization as necessary.

In a similar manner, other 3-keto-A -steroids may be produced from 3-keto steroids. For example, 1118,21- dihydroxy 16oz,17a difiuoromethylenepregn-4-ene-3,20- dione is produced from the corresponding 3-keto steroid.

Example IV To a suspension of 1 g. of 11/3-hydroxy-l6a,17a-difluoromethylene-21-acetoxypregn-4-ene-3,20-dione in 7.5

ml. of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. The mixture is stirred at room temperature for 30 minutes. There is then added 0.8 ml. of pyridine, followed by water until solidifications occurs. This solid is collected by filtration, washed with water and air dried to yield 3-ethoxy-11B-hydroxy-16a,17a-difluoromethylene-21-acetoxypregna-3,5-dien-20-one which is recrystallized from acetonezhexane.

The product is added to a mixture of 0.4 g. of anhydrous sodium acetate, 20 ml. of acetone and 6 ml. of water. The solution is cooled to 5 C. and 1.1 molar equivalents of N-chlorosuccinimide and 0.4 ml. of glacial acetic acid are added. The mixture is stirred for 30 minutes at the same temperature and then diluted with water. After being allowed to stand at 0 C. for 15 hours, the solid is collected by filtration, washed with water and dried under vacuum to yield 6,8-chloro-1lfi-hydroxy-16a,17adifluoromethylene-Zl-acetoxypregn-4-ene 3,20 dione which is recrystallized from acetone. The corresponding 6a-chloro compound is obtained by dissolving this compound in glacial acetic acid and introducing a slow stream of anhydrous hydrogen chloride over a period of four hours at a temperature of 15 C. The solid which forms upon pouring this mixture into water is collected by filtration, washed with water and dried to yield Got-chloro- 115 hydroxy 16a,17a difluoromethylene 21 acetoxypregn-4-ene-3,20-dione which is recrystallized from acetonezhexane. Similarly the 6a-fluoro steroid may be prepared from the same starting material.

A stream of perchloryl fluoride is passed through a a solution of 1 g. of 3-ethoxy-l1fl-hydroxy-16a,17a-difluoromethylene 16B methyl 21 acetoxypregna-3,5- diene-20-one in 25 ml. of dimethylformamide, cooled to 0 C., for 5 minutes. After being allowed to slowly attain a temperature of 20 C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed With a saturated aqueous sodium bicarbonate solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue is then chromatographed on alumina to separate the 6u-fluoro and 6fl-fluoro isomers. The latter, which predominates, is dissolved in 50 ml. of glacial acetic acid and through this is passed a stream of dry hydrogen chloride for a period of 24 hours at a temperature of 15 C. The mixture is poured into cold water and the solid which forms is collected by filtration, washed with water and dried to yield Got-fluoro- 11 3-hydroxy 16a,17a difluorornethylene-l6B-methyl-21- acetoxypregn-4-ene-3,20-dione which is recrystallized from acetonezhexane.

Similarly, 60c chloro 11,8 hydroxy-16a,17u-difiuoromethylene 16,8 methyl 21 acetoxypregn 4 ene-3,20- dione and 6a-fluoro-1lfi-hydroxy-l6a,17a-difluoromethylene-16;3-methyl-21-acetoxypregn-4-ene-3,20-dione are prepared from the corresponding 3-keto-A -steroids.

Example V One gram of 6a-fluoro-115,21acetoxy-16u,17a-difluoromethylenepregn-4-ene-3,20-dione is dissolved with slow heating in 12.5 ml. of dimethylformamide. The mixture is cooled and 0.42 g. of methylchloride and 0.5 ml. of pyridine are added. The solution is heated at C. for 30minutes, then cooled, diluted with water and extracted with ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated to yield 6afluoro 16a,17ot difluoromethylene-Zl-acetoxypregna- 4,9(11)-diene-3,20-dione, which is added to a. mixture of 10 ml. of pure dioxane and 0.16 ml. of 0.4 N perchloric acid.

Five hundred and sixty milligrams of N-bromoacetamide are added over a one hour period with stirring, in the dark and at room temperature, to the mixture; the reaction mixture is then stirred for an additional hour and a solution of 10% sodium sulfite is then added until negative to potassium-starch indicator paper. Ice is added and the mixture extracted with chloroform. These extracts are washed consecutively with water, 5% aqueous sodium bicarbonate solution and water, and the solvent is then removed by distillation in vacuo. The residue is triturated with acetone to yield the bromohydrin intermediate.

A mixture of 0.4 g. of anhydrous potassium acetate :and 4 ml. of acetone is heated almost to boiling and a solution of 0.34 g. of the bromohydrin intermediate, in 4 ml. of acetone, is then slowly added with stirring. The mixture is refluxed for 10 hours, cooled and almost all of the acetone is removed by distillation. Iced water is then added and the solid which forms is collected by filtration, washed with water and dried to yield 6ot-fiuoro-95,115-oxido-16a, 17oz difluoromethylene 21 acetoxypregn 4 ene 3, 20-dione, which may be Lturther purified through recrystallization from methylene chloridezhexane.

The product is dissolved in 30 ml. of methylene chloride, cooled to C., and while being stirred, a cooled so- =lution (-70 C.) of 2.11 g. of anhydrous hydrogen fluoride in 3.7 ml. of tetrahydrofuran is added over a period of 20 minutes. The mixture is stirred at a temperature below 10 C. for 6 hours and then neutralized 'by the cautious addition of aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried over sodium sulfate and concentrated until a solid forms. The cooled mixture is then filtered and the solid dissolved in hot ethyl acetate. This solution is filtered hot and then cooled and the solid which forms is collected by filtration to yield 60:,90c-difl110IO-1l 3-hydf0Xy-l6a,17ot-difiuoromethylene 21 actoxypregn 4 ene 3,20 dione. Alternatively the 9a-chlorosteroid can be formed from the same starting material.

To a stirred solution of 4 g. of 6a-fluor0-95,115-oxido- 1611,1704 difluoromethylene 21 acetoxypregn 4 ene- 3,20-dione in 40 ml. of anhydrous chloroform, hydrogen chloride gas is added over a period of 35 minutes and at 0 C. and then diluted with water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated under reduced pressure to yield 6a-fi1101O-9otchloro 115 hydroxy 16a,17a difluoromethylene 21- acetoxypregn-4-ene-3,20-dione.

By the above procedures, other 9a-chloro or fluoro steroids may be prepared. For example, 6a,9a-dichloro- 115 hydroxy 160:,17u difluoromethylene 21 acetoxypregn 4 ene 3,20 dione, 6oz chloro 90c fluoro- 115 hydroxy 160:,170: difluorornethylene 21 acetoxypregn 4 ene 3,20 dione; 611,90: difluoro 115- hydroxy 1601,17 difluoromethylene 165 methyl 21- acetoxypregn 4 ene 3,20 dione; 9a chloro 115- hydroxy -16oc,17a difiuoromethylene 165 methyl 21- acetoxypregn 4 ene-3,20-dione; 9a-fiuoro-1l5-hydroxyl6u,l7 x-difluoromethylene 165 methyl 21 acetoxypregn 4 ene 3,20 dione; 6a methyl 9a chloro- 115 hydroxy-16a,17u difiuoromethylene-Zl acetoxypregn 4 ene 3,20 dione; 611,165 dimethyl 9achloro 115 hydroxy l6u,17a difiuoromethylene- 21 acetoxypregn -4 ene 3,20 dione; and 60:,165 dimethyl 9a fluoro 115 hydroxy 16a,17a difluoromethylene 21 acetoxypregn 4 ene 3,20 dione are prepared from the corresponding 3-keto-A -steroids by the above appropriate procedure.

Example VI To a stirred solution of 1.6 g. of 21-acetoxy-16a,17adifiuoromethylenepregna-4,9(l1)-diene-3,20-dione and. 4 ml. of chloroform, a solution of 0.3 g. of chlorine in 10 ml. of carbon tetrachloride is added over a 5 minute period with continuous stirring. After being allowed to stand at room temperature for 20 minutes, the mixture is treated with 10 ml. of 5% aqueous sodium carbonate solution and extracted with chloroform. The chloroform extracts are washed with Water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 9a,

dichloro 1611,17 difiuoromethylene 21 actoxypregn-4-ene-3,20-dione which may be recrystallized from acetonezhexane.

Other 9:1,115-di6l1l01'0 steroids may be obtained by using the corresponding M -steroids in the above procedure. For example, 60t,9u,1IB-UlChlOIO-l6a,17ot-dlfluO- romethylene 21 acetoxypregn 4 ene 3,20 dione may be obtained from 6rx-chloro-l6a,17a-difluoromethylene 21 acetoxypregna 4,9(11) diene 3,20 dione by the method of this example.

Example VII A mixture of 0.5 g. of 6a-chloro-115,21-dihydroxy- :,17oc difluoromethylenepregn 4 ene 3,20 dione, 10 ml. of dioxane, and 0.35 g. of 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone is refluxed for 10 hours. The mixture is then cooled, filtered and evaporated to dryness. The residue is dissolved in acetone and this solution is then filtered through 10 g. of alumina and concentrated to yield 60: chloro 115,21 dihydroxy 16or.,17oc difiuoromethylenepregna-l,4-diene-3,20-dione which is further purified by recrystallization from acetonezhexane,

Similarly, 115,21 dihydroxy 160:,170: difiuoromethylenepregna 1,4 diene 3,20 dione; 115,21 dihydroxy 16a,17a difluoromethylene methylpregna- 1,4 diene 3,20 dione; 6a-fluoro 115,21 dihydroxy- 16a,17a difluorornethylene 165 methylpregna 1,4- diene 3,20 dione; 6a-methyl 115,21 dihydroxy- 165, difluoromethylenepregna 1,4 diene 3,20- dione; 9a fluoro 115,21 dihydroxy 16a,17a difluoromethylenepregna 1,4 diene 3,20 dione; 90:,11'5- (l1ChlOI0-160c,l7ot difluoromethylene 165 methyl 21- hydroxypregna 1,4 diene 3,20 dione; and 6:1,9oadlChlOI'O-160t,170t difluoromethylene 165 methyl 21- enepregna-1,4-diene-3,20dione are prepared from the corresponding 3-keto-A -steroids.

Example VIII A mixture of l g. of 6a-fluoro-115,21-dihydroxy-16a, 17a-difiuorornethylene 165 methylpregn 4 ene 3,20- dione, 2 g. of chloranil, and 10 ml. of Xylene is refluxed under an atmosphere of nitrogen for 16 hours. The mixture is cooled, washed with a cold 10% sodium hydroxide solution and then water, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on neutral alumina and further purified through recrystallization from acetonezhexane to yield 6- fiuoro 115,21 dihydroxy 160;,175 difiuoromethylene- 165-methylpregna-4,6-diene-3,ZO-dione.

115,21 dihydroxy 160:,1741 difluoromethylenepregna- 4,6 diene 3,20 dione; 115,21 dihydroxy 16a,170tdifluoromethylene 165 methylpregna 4,6 diene 3, 20 dione; 6 fluoro 115,21 dihydroxy 16a,17u-difluoromethylenepregna 4,6 diene 3,20 dione; 6- methyl 115,21 dihydroxy 160;,17u difluoromethyl enepregna 4,6 diene 3,20 dione; 6,165 dimethyl- 115,21 dihydroxy 16u,17a difluoromethylenepregna- 4,6 diene 3,20 dione; 9m fluoro 115,21 dihydroxy- 16a,17u difiuoromethylenepregna 4,6 diene 3,20- dione; 9a fluoro 115,21 dihydroxy 16a,17a difiuoromethylene 165 methylpregna 4,6 diene 3,20- dione; 9oz fluoro 115,21 dihydroxy 1611,1711; difluoromethylene 165 methylpregna 4,6 diene 3,20 dione; 6,9ot difiuoro 115,21 dihydroxy 16a,17u difiuoromethylenepregna 4,6 diene 3,20 dione; 6,9:- difiuoro 115,21 dihydroxy 16oz,17ot difluoromethylene 165 methylpregna 4,6 diene 3,20 dione; 6- methyl 9oz fluoro 115,21 dihydroxy 16u,17a di fluoromethylenepregna 4,6 diene 3,20 dione; 6,165- dimethyl 91x fluoro 115,21 dihydroxy 16a,17otdifluoromethylenepregna 4,6 diene 3,20 dione; and 9a,115 dichloro 115,21 dihydroxy l6ot,17u difluoromethylenepregna-4,6-diene-3,ZO-dione are prepared in a like manner from the corresponding 3-keto-A steroids.

9 Example IX To a cooled solution C.) of 3.4 g. of 6a,9a-difluoro- 1119,21 dihydroxy 16a,17a difluoromethylenepregn 4- ene-3,20-dione in 20 ml. of 9:1 chloroformzpyridine is added in small portion 1.4 g. of methanesulfonyl chloride. The reaction mixture is allowed to stand for 14 hours at 0 C. and is then washed with dilute hydrochloric acid, water and sodium bicarbonate solution. The chloroform is removed by evaporation under reduced pressure and the residue is dissolved in 20 ml. of acetone which is treated at room temperature and under stirring with 4 g. of sodium iodide. Sodium thiosulfate solution is added to decolorize the mixture, followed by the addition of water. The solid which forms is collected by filtration and dried under vacuum to yield 6a,9a-difluoro-11,8-hydroxy- 16a,l7a-difioromethylene-21 iodopregnane 3,20 dione. This material is dissolved in 20 ml. of acetonitrile and treated in a dropwise fashion with 1.4 g. of silver fluoride in 3 ml. of water. The mixture is allowed to stand at room temperature for 24 hours and then is filtered. The filtrate is concentrated under vacuum and the solid which forms is collected and dried to yield 6a,9a,21-trifluoro-1l 8- hydroxy l6oc,17ot difluoromethylenepregn-4-ene-3,20-dione which is recrystallized from methanolzacetone.

Similarly, 11,8 hydroxy-16a,l7ot-difluoromethylene-21- fiuoropregn-4-ene-3,20-di0ne is prepared from 1113,2l-dihydroxy-16ix,17a difluoromethylenepregn 4 ene 3,20- dione.

Example X A solution of 200 mg. of 9a,11fl dichloro-16a,l7a-difiuoromethylene 16,8 methyl-2l-fiuoropregna-4,6-diene- 3,20-dione in 32 ml. of anhydrous isopropanol and 25 mg. of sodium borohydride is stirred at room temperature for hours. One hundred ml. of water is added and the resulting suspension is extracted several times with ether. The ether phase is dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 3B-hydI'OXy-9OL,11,3-diChlOI'O-160t,17a difiuoromethylene 16B- rnethyl-21-fiuoropregna-4,6-dien-20-one which may be further purified by recrystallization from ether.

Similarly, 9a-fluoro-11B,21-dihydroxy16a,17a,difluoromethylene-1fi-methylpregna-l,4-diene-3,20-dione may be reduced to 35,113,21-trihydroxy-9a-fluoro-16u,17u-difluoromethylene-16,6-methylpregna-1,4-dien--one.

Example XI A mixture of 1 g. of 35,1 1fi-dihydroxy-16a,17a-difiuoromethylene-2l-fluoropregna-1,4-diene-20-one, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3 ,B-acetoxyllfi-hydroxy-l6a, 17a-difiuoromethylene-21-fiuoropregna- 1,4-dien-20-one which may be further purified recrystallization from acetone:hexane. Similarly other 3B-acetoxy and/or 2l-acetoxy steroids may be obtained from the corresponding 3,6-hydroxy and/ or 21-hydroxy steroids. For example, 35,21-diacetoxy 115 hydroxy 16a,l7a-difluoromethylenepregn-4- en-20-one is produced from the corresponding 35,2l-dihydroxy steroid.

By using other other anhydrides in place of acetic anhydride, other acyloxy steroids are produced. For example in the above preparation, if caproic anhydride is used, 3,3-caproxy-11 3-hydroxy-16e,17a difiuoromethylene 21- fluoropregna-1,4-diene-20-one is obtained.

Example XII A mixture of 2 g. of 35,11B-dihydroxy-6a,2l-difiuoro- 16oz,17a-difluoromethylenepregna-l,4-dien-20-one in 8 ml. of pyridine and 4 ml. of adamantoyl chloride is heated at steam bath temperatures for one hour. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3B-adamantoyloxy-6a,2l-difiuoro-11B-hydroxy-16a,-

17 a-difluoromethylenepregn-1,4-diene-20-one which is further purified through recrystallization from methylene chloridezhexane.

Other 3,8-hydroxy and/or 21-hydroxy steroids may be similarly esterified with adamantoyl chloride. For example, 35,2l-diadairnantoyloxy-6-fluoro-11fl-hydroxy-16u, 17a-difluoromethylenepregna-4,6-dien-20-one is prepared from 35,1 15,21-trihydroxy-6-fluoro-16a,17a-difiuoromethylenepregna-4,6-dien-20-one.

Example XIII Two milliliters of dihydropyran are added to a solution of 1 g. of 35,116,21-trihydroxy-16a,17u-difluoromethylene-16B-methylpregna-1,4,6-trien-20-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days, and is then Washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3,B,21-di(tetrahydropyran-2-yloxy) 11p hydroxy 16u,17u difluoromethylene-16/3-methylpregna-1,4,6ltrien-ZO-one which is recrystalized from pentane.

By using dihydrofuran in the procedure instead of dihydropyran, 3 ,B,21 di(tetrahydrofuran 2-yloxy)-11B-hydroxy-l6a,17u-difiuoromethylene-16,8-methylpregna-1,4,6- trien-20-one.

Similarly other 3;? and/or 21-tetrahydropyran or furanyl ether steroids may be prepared from the corresponding 313 and/or 21-hydroxy steroids.

Example XIV 4-ene-3,20-dione which is collected by filtration and recrystallization \from acetone2hexane.

Example XV A mixture of 1 g. of 6a-methyl-16a,17a-difiuoromethylene-Zl-acetoxypregn-4-ene-3,11,20-trione, 25' ml. of dry benzene, 5 ml. of ethylene glycol and 50 mg. of p-toluenesulfonic acid monohydrate is refluxed for 16 hours using a Water separator. The reaction mixture is then washed with aqueous sodium bicarbonate solution and water, dried and evaporated to dryness to yield 3,20-bisethylenedioxy 6a methyl l6a,l7a difluoromethylene 21- acetoxypregn-4-en-l1-one which is recrystallized from acetonezhexane.

A solution of 1 g. of 3,20-bisethylenedioxy-6or-methyl- 16a,17a difluoromethylene 21 acetoxypregn 4 enll-one in 10 ml. of anhydrous tetrahydrofuran is cooled to 75 C. in a Dry Ice-acetone bath and treated with a previously cooled solution of 0.3 g. of lithium aluminum t-butoxide in 10 ml. of anhydrous tetrahydrofuran. After maintaining the reaction mixture at 75 C. for 1 hour and at room temperature for 30 minutes it is poured into ice water and extracted several times with ethyl acetate. These extracts are washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is chromatographed and recrystallized from acetone:hexane to yield 3,20-bisethylenedioxy 6a methyl 16a,l7a difluoromethylene 21- acetoxypregn-4-en-l 1 13-01.

The steroid is then added to 25 ml. of acetone containing 0.1 ml. of concentrated hydrochloric acid. The mixture is allowed to stand for 15 hours then poured into water. The mixture is extracted with methylene chloride, and the extracts are Washed to neutrality, dried and evaporated to dryness to yield fia-methyl-llB-hydroxy-l6a, 17a difluoromethylene 21 acetoxy pregn 4 ene- 3,20-dione.

In a similar manner, the ll-keto steriods of the previous examples can be reduced to the corresponding ll-hydroxy steroids.

For example, 6a,9a-difiuoro-llfi-hydroxy-l6a,l7u-difluoromethylene 21 acetoxypregna 1,4 diene 3,20- dione is obtained from 6a,9u-difiuoro-l6u,l7a-difluoromethylene-21-acetoxypregna-1,4-diene-3,1 1,20-trione.

What is claimed is:

1. Compounds of the formula:

wherein each of Z and Z is a carbon-carbon bond or a carbon-carbon double bond;

R is hydrogen, hydroxy, fiuoro, hydrocarbon carboxylic acyloxy, tetrahydrofuran-Z-yloxy or tetrahydropyran-Z-yloxy;

R is hydrogen or methyl;

R is hydrogen, methyl, fluoro or chloro;

R is hydrogen, fluoro or chloro;

R is oxygen or the group R E where R is hydrogen, hydroxy, hydrocarbon carbo-xylic acyloxy, tetrahydrofuran-Z-yloxy or tetrahydropyran-Z-yloxy; and

R is oxygen or the group R E where R is hydroxy or chloro, R being chloro when R is chloro.

2. Compounds according to claim 1 wherein R is the group 3. Compounds according to claim 1 wherein R is methyl, fluoro or chloro.

4. Compounds according to claim 1 wherein R is hydroxy, fiuoro or acetoxy;

R is hydrogen;

R is hydrogen, fluoro or chloro;

R is oxygen;

R is the group and Z is a carbon-carbon single bond.

5. Compounds according to claim 4 wherein R and R are hydrogen; and

Z is a carbon-carbon single bond.

6. Compounds according to claim 4 wherein R and R are hydrogen; and

Z is a carbon-carbon double bond.

7. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydrogen;

R and R are chloro; and

Z is a carbon-carbon single bond.

8. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydrogen;

R and R are chloro; and

Z is a carbon-carbon double bond.

9. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R and R are chloro; and

Z is a carbon-carbon single bond.

10. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R and R are chloro; and

Z is a carbon-carbon double bond.

11. The compound according to claim 4 wherein R is fluoro;

R is hydrogen;

R and R are chloro; and

Z is a carbon-carbon double bond.

12. The compound according to claim 4 wherein R and R are fluoro;

R and R are chloro; and

Z is a carbon-carbon double bond.

13. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R and R are hydrogen;

R is hydroxy; and

Z is a carbon-carbon single bond.

14. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R and R are hydrogen;

R is hydroxy; and

Z is a carbon-carbon double bond.

15. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydrogen;

R is hydroxy; and

Z is a carbon-carbon single bond.

16. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydrogen;

R is hydroxy; and

Z is a carbon-carbon double bond.

17. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydrogen;

R is hydroxy; and

Z is a carbon-carbon single bond.

18. Compounds according to claim 4 wherein R is hydroxy or ac etoxy;

R is hydrogen;

R is hydroxy; and

Z is a carbon-carbon double bond.

19. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydroxy; and

Z is a carbon-carbon single bond.

20. Compounds according to claim 4 wherein R is hydroxy or acetoxy;

R is hydroxy; and

Z is a carbon-carbon double bond.

21. Compounds according to claim 1 wherein R is hydroxy, fluoro or acetoxy R is methyl;

R is oxygen;

R is the group 13 and Z is a carbon-carbon single bond.

22. A compound according to claim 21 wherein R is acetoxy;

R is hydrogen;

R is hydrogen;

R is hydroxy; and

Z is a carbon-carbon single bond.

23. A compound according to claim 21 wherein R is acetoxy;

R is hydrogen;

14 R is hydroxy; and Z is a carbon-carbon double bond.

References Cited 5 UNITED STATES PATENTS 3,232,961 2/1966 Kaspar et a1 260-3973 HENRY A. FRENCH, Primary Examiner 10 US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 .457 285 Dated July 22, 1969 Invent -(8) Colin C. Beard and Alexander D. Cross It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1]., line 29, between the word "carbon" and "bond", should appear -single-.

SIGNED AND SEALED JUN 2 31970 6 Attesu Edward M. Fletcher, 1:. LIAM Attesting Officer co f m nfi. 

